Rheumatoid arthritis (RA) is a common disease that causes important suffering, disability and increased mortality, and represents an example of a chronic inflammatory immune response. RA is characterized by the overproduction of hyaluronan (HA) and production of low molecular weight HA oligosaccharides which have proinflammatory properties. Nitric oxide (NO) and TNFalpha are two important inflammatory mediators in RA. The mechanisms that induce NO production in human synovial macrophages and the downstream inflammatory effects of NO are poorly understood, especially in the context of diseases such as RA. Likewise, the mechanisms that perpetuate the continued production of TNFalpha in RA have not been completely characterized. This proposal will test the postulate that low molecular weight HA oligosaccharides perpetuate an inflammatory cycle of nitric oxide (NO) and TNFalpha production by synovial macrophages in RA, via the cell surface HA receptor CD44, that leads to further production of fragmented HA oligosaccharides. The specific aims are to: 1.) Compare the ability of HA oligosaccharides of different molecular weight to induce NO production by human monocytes and tissue macrophages. 2.) Determine whether HA oligosaccharides induce NO production by monocytes and synovial macrophages from patients with RA. 3.) Determine the ability of HA oligosaccharides to induce human macrophage cytokine production. 4.) Determine whether NO production by monocytes and synovial macrophages induces HA fragmentation. These studies will lead to future work that defines the molecular events involved in CD44 signaling and NO production by human macrophages and will also provide the rationale for therapeutic trials in RA patients that target inhibition of NO production and inhibition of CD44-HA interactions.